Cell cycle activation in p21 dependent pathway: An alternative mechanism of organophosphate induced dopaminergic neurodegeneration

Willayat Yousuf Wani, Ramesh J.L. Kandimalla, Deep Raj Sharma, Alka Kaushal, Anand Ruban, Aditya Sunkaria, Jayalakshmi Vallamkondu, Alberto Chiarugi, P. Hemachandra Reddy, Kiran Dip Gill

    Research output: Contribution to journalArticlepeer-review

    7 Scopus citations

    Abstract

    In the previous study, we demonstrated that dichlorvos induces oxidative stress in dopaminergic neuronal cells and subsequent caspase activation mediates apoptosis. In the present study, we evaluated the effect and mechanism of dichlorvos induced oxidative stress on cell cycle activation in NGF-differentiated PC12 cells. Dichlorvos exposure resulted in oxidative DNA damage along with activation of cell cycle machinery in differentiated PC12 cells. Dichlorvos exposed cells exhibited an increased expression of p53, cyclin-D1, pRb and decreased expression of p21suggesting a re-entry of differentiated cells into the cell cycle. Cell cycle analysis of dichlorvos exposed cells revealed a reduction of cells in the G 0 /G 1 phase of the cell cycle (25%), and a concomitant increase of cells in S phase (30%) and G2/M phase (43.3%) compared to control PC12 cells. Further, immunoblotting of cytochrome c, Bax, Bcl-2 and cleaved caspase-3 revealed that dichlorvos induces a caspase-dependent cell death in PC12 cells. These results suggest that Dichlorvos exposure has the potential to generate oxidative stress which evokes activation of cell cycle machinery leading to apoptotic cell death via cytochrome c release from mitochondria and subsequent caspase-3 activation in differentiated PC12 cells.

    Original languageEnglish (US)
    Pages (from-to)1858-1866
    Number of pages9
    JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
    Volume1863
    Issue number7
    DOIs
    StatePublished - Jul 2017

    Keywords

    • Cyclin-D1
    • Dichlorvos
    • Neurodegeneration
    • Oxidative stress
    • p21

    ASJC Scopus subject areas

    • Molecular Medicine
    • Molecular Biology

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